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Diagnostic defense

Battling biological threats at home and abroad

The U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID; Fort Detrick, MD) aims to protect the U.S. military against biological threats on the battlefield. As the lead laboratory of the Department of Defense (DoD; Washington, DC) for biological warfare defense, USAMRIID devotes significant effort to developing both laboratory and field diagnostic assays for biological warfare agents.

In an interview with IVD Technology editor Steve Halasey, Colonel Erik A. Henchal, chief of the diagnostic systems division at USAMRIID, discusses the how the organization works within the myriad departments aimed at protecting public health and why USAMRIID's latest technological developments on the military front translate into viable clinical applications on the home front. The complete text of this interview is also available.

IVD Technology: In the healthcare community at large, including both product manufacturers and clinicians, the role of diagnostics is often under-appreciated. How would you rate the importance of diagnostics in the realm of biodefense activities?

Erik Henchal: It is at the core of our response to bioterrorism. I don't think that we can properly protect and treat the public unless we have good diagnostics and identification tools.

USAMRIID's activities are really designed for military personnel. What is the connection between those efforts and the public at large?

In the case of field laboratories, military requirements closely duplicate what would happen in a doctor's office or an emergency room. That is the best crossover between what we're doing for the military and how it applies to the public at large.

I'm a big fan of point-of-care devices. If clinical laboratories take too long to get results to care providers, they may become less important to physicians. Very few laboratories can perform bacterial agent identification and turn results around to a physician in less than 24 to 48 hours. As a result, physicians often move forward and begin treatment without a confirmed diagnosis.

It's critical that all of the technology available is used to develop identification tools that enable physicians to confirm diagnosis as soon as possible. Once these tools are available, disease outcomes will improve.

What characteristics would you consider important for a successful biodefense diagnostic?

Four performance characteristics are critical. First, the diagnostic should be rapid, which means agent identification should be performed in less than an hour.

Second, it should be sensitive—any new device or technology should identify the organisms within the clinical range, or at least to a point where we can estimate the infectious dose of the organism.

Third, a successful biodefense diagnostic should be specific, so that the physician or the first responder can implement the appropriate countermeasures. If it's not specific, then why use it?

Finally, it should be reliable. It should be able to work under a variety of different environmental conditions and in the hands of unskilled users if necessary. It should be able to reproducibly identify the organisms within an acceptable range.

Do the characteristics of a successful biodefense diagnostic differ according to the agents that it's designed to detect, or can one diagnostic be used to detect multiple agents?

We have a philosophy at USAMRIID that no single diagnostic approach is sufficient for a definitive identification. Overlapping diagnostic technologies are needed to reach a confident identification. For example, we use a combination of gene amplification, immunodetection, and culture techniques to reach a high confidence level in our results. Future systems will have to do the same thing.

No single available technology can identify all the different agents. The types and varieties of bioterror agents are quite broad. Popular gene amplification technologies are not sufficient for identifying protein toxins; so future systems must incorporate a minimum of two different technologies just to cover the living agents in protein toxins.

And, future systems will need to incorporate a strong information management system to integrate medical intelligence and the disease characteristics that a physician might observe.

What assumptions should be made about those using the technology? Are they likely to have sophisticated laboratory training or are they first responders with little clinical expertise?

We want tools that are effective in the hands of the nonexpert user. That does not mean the untrained user. The problem is that the United States lacks a sufficient number of people who have experience with the identification of bioterrorism agents. The bulk of agent identification, especially with regard to bioterrorism agents, will depend upon some of these identification technologies being placed in the hands of first responders—emergency room personnel and medical personnel—who are not certified clinical laboratorians.

There's still a role for those in the confirmatory realm of diagnostics, but in order to have a real impact on public health and public safety, I think we have to expect that some of the tools will have to be in the hands of the first responder, especially the emergency room personnel—people who have to respond quickly to a bioterrorism event.

Communication Is Key

One of the things that of course happened on September 11 was that communications systems in New York were a mess. What special challenges does a communications dilemma pose for organizations like USAMRIID?

Probably one of the biggest challenges we had last fall was being able to communicate results in a timely fashion to the decision makers. At USAMRIID, we only overcame that by frequent e-mails, telephone conferences, and personal contact. The second greatest challenge was being able to tell what was going on in other cities. For a period of time, we were somewhat isolated. We did not know what was going on in New York City while we were trying to respond in Washington, DC.

At times, it was very difficult to communicate with the Centers for Disease Control and Prevention (CDC; Atlanta) and others responding to the emergency. There was no unifying system to communicate across all of the different communities of people who had to respond. There was a great gap in our knowledge. The CDC's ability to answer the hard questions for those exposed to anthrax could have been enhanced by better communication with other crisis responders, such as the military.

Is there a technological fix for this communication lag? If so, who is in charge of it?

There are new networking systems being attempted. The CDC is installing different kinds of electronic systems for exchanging information. That will help as long as the phone lines and the Internet systems linking hospitals into the networks are functioning.

This may be effective in different metropolitan areas. Ultimately, the various responding organizations will have to be tied to some great information-sharing network, either through wireless systems or whatever it takes to communicate in real time when responding to a bioterrorism event.

USAMRIID has teams that can get to an emergency site in 12 hours, but that's 12 hours in which somebody else is responding. Do you expect that local authorities will still have a significant role to play as first responders and coordinators of activities?

Local authorities will definitely play a significant role. Centralized systems of response are not feasible. Technology should be pushed as far as possible to the local level in order to have an effective response to bioterrorism.

Limits of the Field

How have the differences between field diagnostics and laboratory diagnostics, and between local resources and federal resources, influenced the selection of new technologies to be adopted for use at the local level?

In the past 10 years, there has been a lot of emphasis in the commercial diagnostic sector on the development of high-throughput devices. Generally, those high-throughput strategies are designed for centralized clinical laboratories or to support big pharmaceutical interests and aren't appropriate for the first responder. USAMRIID's interests in the last five years have been to develop smaller, self-contained systems that can be used outside the big laboratories. There's a need for both single-use systems and the high-throughput systems.

One of the lessons learned last fall was that the single-use technology could have been used during the local response, but in the consequence-management phase, high-throughput devices were necessary for rapidly screening an entire building or for multiple sampling, such as trying to assess the limits of detection in the Senate or at the New York Post.

Chain of Command

What is the relationship between USAMRIID and the CDC, the National Institutes of Health (NIH; Bethesda, MD), and especially the National Institute of Allergy and Infectious Diseases (NIAID; Bethesda, MD), which is the chief civilian authority for bioterrorism issues?

USAMRIID is what we call a Level D laboratory in the National Laboratory Response Network that's sponsored by CDC. We are partners with CDC, and in the early phase of setting up the network, a lot of technologies that were developed in the Department of Defense were transferred to the CDC to help them establish the network.

We are developing relationships with NIAID and NIH, which will lead to future development of technologies and products that we need. NIH and CDC are still focused on treatment of disease, while the military is focused on prevention through the use of prophylactic drugs, early diagnosis, and therapeutics. However, the two systems are quite similar.

Do you feel USAMRIID was contacted in a timely matter after the initial anthrax infections occurred in Washington, DC, and elsewhere? Considering USAMRIID had the best ability to identify this agent and where it might have come from, were other agencies slow in contacting you?

That was not what actually happened. We were contacted very close to the beginning of the incidents. For example, we had the letter containing anthrax that was sent to Senator Tom Daschle (D–SD) in hand within hours after it was collected by law enforcement officials. We had immediate contact with the FBI and assessed risk fairly quickly. Afterward, we held two telephone conferences daily with all of our federal partners to share our results. By doing this, we could also track what the other agencies were doing.

USAMRIID is not meant to be a front-line patient-care provider and so it was appropriate at the time, for example, during the incidents on Capitol Hill, that some of the other facilities be involved, such as the Walter Reed Army Medical Center (Washington, DC) and the National Naval Medical Center (Bethesda, MD). They played big roles early on in responding to the threat. Our relationship has been primarily with the FBI. We support the other investigative aspects of bioterrorism incidents.

So you feel that the coordination of the various federal partners is working and will get better?

I never had many complaints about USAMRIID's interaction with the other federal partners. Because we work with law enforcement, the kind of information we could share was limited. Our response wasn't meant to lead a consequence-management response for these threats.

Our role at that time was primarily service support to those organizations that asked us for help, like the FBI. We were often criticized for giving information only to our customer without sharing it with the public. But it wasn't appropriate for us to be advertising our role upfront. At the time, the FBI was in charge of the investigation and our role was to support them and the CDC. We weren't in any position to try to be a leader or take a first-level role at that point.

Working with Industry

USAMRIID works with a lot of academic institutions and clinical partners. Does the institute also work with industry partners?

For medical diagnostics we have a long list of commercial partners—companies that have research and development agreements with us, and small businesses that are involved in developing new technologies. I've been a research coordinator for diagnostic products since 1997 and USAMRIID has a great relationship with a variety of commercial companies and academic laboratories in order to test and evaluate a variety of diagnostic technologies.

Does USAMRIID set up the criteria for some of the projects headed by the Defense Advanced Research Projects Agency (DARPA) and its Advanced Technology Office?

No, we don't set up any criteria. USAMRIID, the DARPA program, and the other R&D areas are focused on the development of new technologies. Very often our scientists, as subject matter experts, are asked to review and evaluate whether those new technologies are ready for quick deployment. Then put them in the hands of our diagnostic laboratories with a military application in mind.

How do you handle intellectual properties? Do you have a lot of shared patents with industry? Usually when the government funds something, it expects to own it.

That's not necessarily true. We enter into cooperative research and development agreements that are structured to protect the interests of the partners. Usually that means the commercial companies have a right to the things they develop and are unique to their company. The military and the government get the rights to the technologies that they develop and then there is usually a joint arrangement.

This might take the form of exclusive worldwide commercial rights to a particular technology. We don't try to own everything. It doesn't make good business sense to do that. In fact, we want our commercial companies to be successful, because that's how they're going to improve on and make the products we need. The military is a much smaller market than the greater diagnostic market, and it's important that companies have a very strong commercial base. I know of very few companies that have as their business plan solely to support the government. They just wouldn't be successful.

Future Technology

In addition to anthrax, what kinds of reagents or diseases are you looking into specifically as bioterrorism threats?

My program actually covers a much broader array of threats than just anthrax. We have developed integrated diagnostic systems including the protocols, reagents, and devices to identify 26 different biological agents.

We have a unique role in that we support some field laboratories. One of the problems with the field laboratory is that there are about 50 different infectious diseases to identify. We found early on that it was a logistical burden to put so many different diagnostic technologies in the field laboratory because of the limited space and weight capability. We couldn't put in 50 different diagnostic assays, so we've been developing what we call "core" or "common" diagnostic systems that can address as many bioterrorism threats as possible.

Many of our diagnostic approaches are focused on a few basic technologies, such as simple enzyme-linked immunosorbent assays with common formats for different diseases or common PCR assays, so that the laboratories only need a small number of technologies. That is more supportable from a logistical standpoint.

Are these primarily cartridge-based formats?

That is certainly a part of the research and development that we're doing. A lot of that particular cartridge-based development doesn't exist in our laboratories yet, but it is certainly among the new technologies that we're working with.

We've been working with a company called Cepheid (Sunnyvale, CA) that has developed integrated cartridges that can do rapid specimen processing and gene amplification in a single, one-step cartridge. It's really a terrific prototype and we're working with the company to improve that.

We have also been working with Idaho Technologies (Salt Lake City) and its Ruggedized Advanced Pathogen Identification Device (RAPID) system to evaluate the company's sample-processing and gene amplification strategy; as well as with IGEN (Gaithersburg, MD), the company that designed the Origen electrochemiluminescence assay. With them, we've been able to develop a 15-minute, one-step assay for a variety of biological agents.

The future of the research is trying to get all of these on the same platform. For example, evolving strategies include microarray technology that allows for much broader screening on a single device.

What are the key challenges to handling the possible threat of genetically mutated organisms that might be used as bioterrorism agents?

Many identification technologies currently available focus only on important genus and species markers. We are trying to develop a lot of depth in the biomarkers that we want to address.

We have simultaneous development in trying to identify new markers—from stable genus and species markers to host response markers. That is probably going to be a new area that we have a lot of interest in. Of course, we are also developing new approaches for looking at and identifying antibiotic resistance. We know that there has been some activity in foreign countries to develop antibiotic resistant organisms for use as biological threats, so our new diagnostic systems are going to have to accommodate that as well.

So you are really attacking it on a very broad front?

We are building a lot of depth in the biomarkers that are available for testing, so we won't be surprised by something new in the future.

Colonel Erik A. Henchal, PhD, is the chief of the diagnostic systems division at USAMRIID (Fort Detrick, MD).

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